To date, little is known about the underlying cellular and molecular mechanisms of progressive hearing loss (PHL) that affects our aging population. Degeneration of hair cells and spiral ganglia neurons (SGNs) are common phenotypes associated with PHL. The importance of K+ channels in the inner ear is underpinned by evidence that specific mutations of the channel result in degeneration of hair cells (HCs) and SGNs in humans. Here, we hypothesize that K+ channels in SGNs regulate the resting membrane potential and their excitability in order to modulate fluxes of intracellular Ca2+ (Ca2+i), which serves as a key second messenger, determining the development, function, and survival of SGNs. However, undue [Ca2+i] may induce neuronal death. We further predict that during aging and in several K+ channelopathies associated with progressive degeneration of SGNs, the expression of K+ channels are profoundly altered leading to membrane depolarization, excessive increased in Ca2+ influx, which triggers Ca2+- induced apoptotic neuronal death. The proposal will identify how homo- and hetero- multimers of K+ channels confer diversity of K+ currents, and how mutations of the pore- forming a-subunit may produce profound alterations of K+ currents. We will also learn how intracellular and single-pass accessory subunits control K+ channels in SGNs. Five specific aims consider; what elementary features of K+ channels in SGNs confer their roles as K+ transporters (Aim 1); what K+ channel subunits constitute native SGN K+ currents (Aim 2); how soluble cytoplasmic proteins, K+ channel interacting proteins (KChIP), regulate the surface expression and properties of K+ channel currents (Aim 3); how single-pass subunits of K+ channels, KCNEs, dictate specific K+ channel functions in health and disease (Aim 4); and the ensuing biochemical and functional changes that occur during aging (Aim 5) that mediates PHL. The proposal uses normal and genetically altered mice as the experimental models, and exploit classical techniques (electrophysiology, biochemistry and electron microscopy) and novel strategies made powerful by recent advances in molecular biology (e.g, siRNA knockdown and viral- mediated gene transfer). Of particular importance to auditory science is the possibility that a rational design of K+ channel subtype-specific drugs may be realized, as our understanding of the gating, permeation, and pharmacology of the channels becomes more refined.